Method for locating on a cornea an artificial lens fabricated from a collagen-hydrogel for promoting epithelial cell growth and regeneration of the stroma

ABSTRACT

A method for locating on a cornea an artificial lens fabricated from a collagen-hydrogel for promoting epithelial cell growth and regeneration of the stroma is shown. The method provides for affixing an artificial lens to the Bowman&#39;s membrane and the lens, during the healing process, promotes and supports epithelial cell growth enabling corneal epithelium of the cornea of an eye to attach to and cover the anterior surface of the lens implanting the same and to regenerate the stroma which grows over the edge of and attaches to the optical lens. Laid down in the layers of the regenerated stroma are new keratocytes and collagen fibial produced from keratocytes. The collagen-hydrogel is a hydrogel polymer formed by the free radical polymerization of a hydrophilic monomer solution gelled and crosslinked in the presence of an aqueous stock solution of collagen to form a three dimensional polymeric meshwork for anchoring collagen. The collagen-hydrogel material has a ratio by weight of collagen-to-hydrogel in the range of about 0.6-to-1000 and less than 0.6-to-1000 but at a level wherein sufficient collagen is present by weight to at least one of promote epithelial cell growth and regeneration of the stroma to produce keratocytes including collagen fibial growth. The collagen-hydrogel material or an artificial lens or contact lens produced therefrom can include a epithelial growth enhancer to promote epithelial cell growth during the healing process.

RELATED APPLICATIONS

This application is a Continuation-in-Part Application of U. S. patentapplication Ser. No. 07/511,847 filed Apr. 6, 1990, now U.S. Pat. No.4,994,081, which is a continuation of U.S. patent application Ser. No.06/920,070 filed Oct. 16, 1986, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a collagen-hydrogel material which contains acollagen-hydrogel for promoting epithelial cell growth and which isadapted to be used to fabricate artificial lens or contact lens whichpromotes healing of corneal epithelium during implantation and moreparticularly to a collagen-hydrogel biomedical material that is formedof a polymerized hydrophilic monomer which is gelled and crosslinked toform a polymeric meshwork in the presence of and anchoring collagenformed of a constituent of ground tissue capable of promoting andsustaining epithelial cell growth and regenerating growth of the stromaand wherein an artificial lens, formed of the collagen-hydrogel forpromoting epithelial cell growth and positioned over the pupillary zoneof the eye contiguous Bowman's membrane having a selected portion ofcorneal epithelium removed therefrom, promotes epithelial cell growthenabling corneal epithelium to attach to and cover the artificial lensto implant the same in the eye between Bowmann's membrane and a newlayer of epithelial cells forming corneal epithelium. Laid down in thelayers of the regenerated stroma are new keratocytes and collagen fibialproduced from keratocytes. This invention particularily relates to amethod for locating on a cornea an artificial lens fabricated from acollagen-hydrogel for promoting epithelial cell growth and regenerationof the stroma.

2. Description of the Prior Art

Before beginning a description of the prior art, it would be helpful, inunderstanding the teachings of this invention, to define certain of thekey terms that are used in the teachings of this invention.

Collagen, in its broadest sense, is a natural protein which serves asthe ground substance or adhesive substance between cells in livingtissue. It is well known in the art that collagen, as a substratematerial, is capable of promoting cell adhesion and growth. Otherproteins are also known to be capable of supporting cell growth of atleast certain cell lines. In the present invention, the preferred sourceof collagen, as a natural protein, is derived from animal sources.

It is also known that other macromolecules, that is a molecule formed ofa constituent of a ground substance of tissue, can support cell growth.Typical of such macromolecules, in addition to collagen, aremucopolysaccnarides or fibronectin, which constituents of groundsubstances of tissue are capable of promoting cell growth.

One class of synthetic materials which have found wide application asbiomaterials is the class known as hydrogels. The term "hydrogel" refersto a broad class of polymeric materials which are swollen extensively inwater, but which do not dissolve in water. Generally, hydrogels areformed by polymerizing a hydrophilic monomer in an aqueous solutionunder conditions where the polymer becomes crosslinked so that a threedimensional polymer network is formed which is sufficient to gel thesolution. Hydrogels are described in more detail in Hoffman, D. S.,"Polymers in Medicine and Surgery," Plenum Press, New York, pp 33-44(1974).

Hydrogels have many desirable properties for biomedical applications.For example, they can be made nontoxic and compatible with tissue. Inaddition, they are usually highly permeable to water, ions and smallmolecules. As is noted herein below, despite these favorable qualities,hydrogels have been found, in general, to be unsuitable as substratesfor cell attachment and growth.

With the benefit of the above described descriptions and definitions,the known prior art will now be addressed.

It is known in the art to utilize a procedure known as epikeratophakiafor the correction of aphakia and high myopia in a human eye(hereinafter referred to as the "pikeratophakia Procedure"). In theEpikeratophakia Procedure, human corneal tissue is used and the cornealtissue is mechanically machined or polished to a specific lens power toform a corneal tissue lens. The corneal tissue lens is then sutured tothe anterior surface of the cornea in the pupillary zone of the eye inorder to change the refractive power of the eye. The specific procedureused for suturing the machined or polished corneal tissue lens to theeye requires that a portion of corneal epithelium be removed to expose aportion of Bowman's membrane and corneal tissue lens then be placeddirectly upon Bowman's membrane. During the healing process, cornealtissue lens is covered by epithelial cells which form the corneaepithelium implanting corneal tissue lens between Bowman,s membrane andcorneal epithelium. This procedure depends on the availability of humancornea tissue.

It is also known in the art to use frozen human corneal tissue, which isground to a lenticular power, to form a corneal tissue lens and tosuture the same to corneal stroma of a human eye to change therefractive power of the eye. This procedure is known as the"keratomileusis" and is described in a published article captioned"Keratophakia and Keratomileusis -Clinical Results" which appeared inAugust 1981, Volume 88, No. 8, at pages 709-715 of American Academy ofOphthalmology by Swinger, Casmir and Barraquer, Jose3 (the"Swinger/Barraquer Publication").

It is also known in the art to use collagen-hydroxyethylmethacrylatehydrogels as substrates for promoting cell growth in tissue culture. Thematerial used for the hydrogel is known ascollagen-hydroxeythylmethacrylic, and referred to as a HEMA hydrogel,which was prepared in the presence of an aqueous solution of nativecollagen. The resulting transparent hydrogel containing collagen wasevaluated as substrata for growth of various cell lines in tissueculture. The preparation and use of collagen-hydroxyethylmethacrylatehydrogels for promoting cell growth in tissue culture is described in aarticle entitled USE A COLLAGEN-HYDROXYETHYLMETHACRYLATE HYDROGEL FORCELL GROWTH which appeared in Volume 77, Number 4, April 1980 at pages2064-2068 of the Proceedings of the National Academy of Science, UnitedStates of America, wherein the authors were Linda Civerchia-Perez (theinventor herein), Barbara Faris, Gary La Pointe, John Beldekas, HowardLeibowitz and Carl Franzblau (the "Civerchia Publication"). TheCiverchia Publication disclosed that thecollagen-hydroxyethylmethacrylate hydrogels for promoting cell growth intissue culture were prepared by polymerizing monomerichydroxyethylmethacylate in the presence of various concentrations ofsoluble native collagen. The resulting transparent hydrogels were usedas substrate for growth of IMR- 90 human embryonic lung fibroblasts. Itwas determined from these experiments that the growth of IMR 90 humanembryonic lung fibroblasts was dose dependent upon the amount ofcollagen contained within the hydrogel. The resulting cell growth becomeintimately attached to the hydrogel substrate, and could not be removed.It was also noted during the experiments leading to the CiverchiaPublication that hydrogels containing albumin, gelatin (denaturedcollagen) or collagenase-treated collagen do not support cell growth.The results of this publication provided a foundation for a relativelyeasy procedure for experimentally probing mechanisms of cell adhesionand cell differention. Substantially the same material is disclosed inU. S. Pat. No. 4,565,784 wherein the inventor hereof is one of theco-inventors of the U.S. Pat. No. 4,565,784.

The use of hydrogels for the correction of refractive error is wellknown in the art, and such hydrogels are used as the base material forfabricating soft contact lens. Soft contact lens are adapted to beinserted into and removed from the eye. When soft contact lens areplaced in the eye of a user, the function thereof is to correct myopia,hyperopia, astigmatism, and aphakia. Typically such contact lens areformed of a hydrogel selected from the hydrophilic class of polymers,and the hydrogel is molded or lathed to a specific lens power. The softcontact lens, when placed over the pupillary zone of the eye of a user,rests upon a tear film and corneal epithelium and function to change therefractive power of the eye.

It is also known in the art to experimentally implant high watercontent, intracorneal implants fabricated from a Vistamarc hydrogel inthe eye of rhesus monkeys and to develop keratometric data therefrom.Typical of publications describing this procedure are (i) an articlecaptioned HYDROGEL KERATOPHAKIA: A FREEHAND POCKET DISSECTION IN THEMONKEY MODEL which appeared in the 1986 Volume 70 issue, at pages187-191 of the British Journal of Ophthalmology by Bernard E. McCarey etal (the "McCarey Publication"), and (ii) an article captioned HYDROGELKERATOPHAKIA: A MICROKERATOME DISSECTION IN THE MONKEY MODEL whichappeared in the 1986 Volume 70 issue, at pages 192-198 of the BritishJournal of Ophthalmology by W. Houdijn Beekuis et al (the "BeekuisPublication"). These publications disclose that hydrogels can beimplanted into the cornea of a monkey and that the hydrogel materialsare compatible with the cornea tissue of a monkey.

U.S. Pat. No. 4,126,904 to Dennis D. Shepard, M. D. discloses artificiallenses, which are hard contact lenses, which are adapted to be placed inthe eye of a user. In addition, U.S. Pat. No. 4,126,904 discloses amethod of locating the same on the cornea of the eye. The disclosedartificial lens has an optical portion, which preferably is circular inshape and dimensioned to overlie the pupillary zone of an eye, and anon-optical portion, termed the "haptic" portion, which is used as ameans for permanently affixing the lens to the eye. As taught by U.S.Pat. No. 4,126,904, the artificial lens can be affixed to the anteriorsurface of the cornea by suturing, stapling or like attachment means forsecuring the lens to adjacent structure of the eyeball so that the lenswill move with the eyeball.

Biologically stablized compositions comprising collagen as the majorcomponent with ethylenically unsaturate compounds used as contact lensis known in the art and are disclosed in U.S. Pat. Nos. 4,452,925 and4,388,428. In these compositions, the ratio of collagen by weight to thecomposition is very high and use of high collagen levels in contact lensmay make the lens cloudy and affect the transparency thereof and are ofsuch high levels that the same are incapable of significantly promotingepithelial cell growth and regeneration of the stroma. These UnitedStates Patents do not disclose, teach or suggest that the concentrationslevels of collagen should be controlled to low levels which are capableof promoting epithelial cell growth and regeneration of the stroma.

It is also known in the art that Chiron Ophthalmics, Inc. has isolated aepithelial growth factor molecule and has used this molecule to apply tothe human eye to produce a more rapid resolution of corneal abrasion.

SUMMARY OF THE INVENTION

None of the prior art discloses, teaches or suggests a collagen-hydrogelwhich is capable of promoting epithelial cell growth when fabricatedinto an artificial lens which is positioned over the pupillary zone ofthe eye contiguous with Bowman's membrane to promote and supportepithelial cell growth enabling corneal epithelium to become attached toand implant the artificial lens between Bowman's membrane and cornealepithelium.

This invention relates to the use of a transparent collagen-hydrogel, asa biomedical material, which is capable of being molded to a givenlenticular power as in the preparation of a contact lens, to produce anartificial lens having a collagen-hydrogel for promoting epithelial cellgrowth. Such an artificial lens is adapted to be sutured, glued, or heldin place with bandage or therapeutic contact lens until the epitheliumgrowth occurs directly to the anterior surface of the cornea directly onBowman,s membrane and functions to correct refractive errors of the eye.The collagen-hydrogel, referred to sometimes herein as a"collagen-hydrogel for promoting epithelial cell growth," will becovered by corneal epithelium during the healing process. The growth ofthe epithelial cells to form corneal epithelium on the anterior surfaceof the eye during the healing process is very similar to thatexperienced in the Epikeratophakia Procedure.

In the present invention, a hydrogel polymer is disclosed that is formedby the free radical polymerization of a hydrophilic monomer solutiongelled and crosslinked to form a three dimensional polymeric meshworkanchoring macromolecules. The macromolecules comprise a constituent of aground substance of tissue, such as a native collagen, interspersedwithin the polymeric meshwork forming a collagen-hydrogel for promotingepithelial cell growth. An optical lens for the eye fabricated from thecollagen-hydrogel, when attached to Bowman's membrane of the cornea ofan eye, is capable of supporting and promoting epithelial cell growthenabling corneal epithelium to attach to and cover an artificial lensformed of the collagen-hydrogel for promoting epithelial cell growthduring the healing process.

Also disclosed herein is an artificial lens, which preferably is acontact lens having a predetermined shape and power, which is fabricatedfrom the collagen-hydrogel biomedical material and which is adapted tobe affixed to Bowman,s membrane of the cornea of an eye. When theartificial lens formed of the collagen-hydrogel for promoting epithelialcell growth is so affixed to the eye, it promotes and supports growth ofepithelial cells across the surface thereof to produce cornealepithelium formed of several layers of epithelial cells. In thepreferred embodiment, the contact lens comprises a lens body havinganterior and posterior surface and formed of a collagen-hydrogel forpromoting epithelial cell growth. The hydrogel comprises a hydrogelpolymer formed by the free radical polymerization of a hydrophilicmonomer solution gelled and crosslinked to form a three dimensionalpolymeric meshwork anchoring macromolecules. The macromolecules comprisea constituent of a ground substance of tissue interspersed within thepolymeric meshwork forming a collagen-hydrogel for promoting epithelialcell growth. The collagen-hydrogel is capable of promoting andsupporting growth of corneal epithelium formed of several layers ofepithelial cells which implant the artificial lens between Bowman'smembrane and corneal epithelium. The lens body is adapted to have theposterior surface thereof positioned over the pupillary zone of the eye,and is affixed to Bowman,s membrane in an area substantially equal tothe shape of the lens body having corneal epithelium removed therefrom.When the lens body is so affixed, it is capable of supporting andpromoting epithelial cell growth enabling corneal epithelium to attachto and cover the anterior surface of the lens body.

Also disclosed herein is a method of fabricating a collagen-hydrogel forpromoting epithelial cell growth. The method comprises the steps offorming a radical free polymer of a hydrophilic monomer; mixing thehydrophilic monomer with a diluted solution of macromolecules comprisinga constituent of ground substance of tissue in the presence of a weaksolution of ammonium persulfate and sodium metabisulfate forming a clearviscous monomer solution; and heating the polymer mixture in thepresence of a crosslinking agent to polymerize the same into a threedimensional polymeric meshwork having macromolecules comprising aconstituent of ground substance of tissue interspersed within the threedimensional polymeric meshwork.

The hydrogel used in the prior art for lenses which are placed onto thecornea of the eye or implanted on the eye have serious disadvantageswhich are overcome by the teachings of this invention.

The Epikeratophakia Procedure and the procedure described in theBarraquer Publication require the use of human corneas as the source ofcorneal tissue. The corneal tissue must be processed into apredetermined shape and power to fabricate an implantable corneal tissuelens. The source of human corneal tissue is limited, and the costthereof is controlled, thereby limiting the availability of the cornealtissue for the Epikeratophakia Procedure and the use of theEpikeratophakia Procedure itself as a readily available alternative.

None of the prior art which disclose the use of collagen-hydrogel forfabricating artificial lens disclose, teach, or suggest the use of acollagen-hydrogel which has been gelled and crosslinked to form a threedimensional polymeric meshwork anchoring macromolecules wherein themacromolecules comprise a constituent of a ground substance of tissueinterspersed within the polymeric meshwork forming a collagen-hydrogelfor promoting epithelial cell growth when the hydrogel is attached toBowman,s membrane of the cornea of an eye. As a result ofcollagen-hydrogel for promoting epithelial cell growth, cornealepithelium is capable of attaching to and covering thecollagen-hydrogel.

The prior art Civerchia Publication discloses the experimental use of acollagen-hydroxyethylmethacrylate hydrogel as tissue growing substratefor promoting tissue cell growth of IMR-90 human embryonic fibroblasts,which are cells harvested from the lungs of a human fetus, as anexperimental means to probe the mechanism of cell adhesion and celldifferention. Thus, the teachings of the Civerchia Publication arelimited to experimental tissue culture applications in that theCiverchia Publication did not recognize, teach, suggest, or discloseeither the concept of or the use of a collagen-hydrogel for promotingepithelial cell growth as a basic material for fabrication of anartificial lens which, when implanted on, or into, the eye, would resultin overcoming rejection of the artificial lens and the promotion of andsupport of the growth of epithelial cells to enable corneal epitheliumto attach to and cover the anterior surface of the artificial lens withseveral layers of epithelial cells to form corneal epithelium resultingin the artificial lens being implanted between Bowman's membrane andcorneal epithelium.

The McCarey Publication and Beekuis Publication disclose theimplantation of artificial lens, using the freepocket dissection methodand the Barraquer method, respectively, wherein the artificial lenseswere fabricated from hydrogels with high water content. The resultsdisclosed by both the McCarey Publication and Beekuis Publication werethat the hydrogels were well tolerated within the corneal tissue. TheBeekuis Publication disclosed that the implantation of hydrogels hadinterface problems along the edge of implant, apparently from tissuebuildup at the boundary layer between the lens/corneal epitheliuminterface. The Beekuis Publication noted that implants with abruptly cutedges versus a fine wedge tended to have more light scattering collagenat the implant margin. The collagen referred to is the native cornealcollagen located within the corneal tissue of the monkey, and to nativecollagen. There is no collagen interspersed within the hydrogelmoleculer structure that was used to fabricate the artificial lensimplanted within the monkeys as described in both the McCareyPublication and Beekuis Publication.

The artificial lens and method for implanting the same disclosed in U.S.Pat. No. 4,126,904 relates to so called "hard contact lens", and thelens are formed of standard plastics or known hard plastics, such aspolymethylmetacrylate (PMMA), none of which contain a collagen-hydrogelfor promoting epithelial cell growth. The concept of surgicallypositioning the artificial lens over the pupillary zone of the eye isapplicable to this invention, it being noted, however, that theartificial lens attached to the eye using the teachings of U.S. Pat. No.4,126,904 results in the lens being affixed to the anterior surface ofcorneal epithelium.

Thus one advantage of the present invention is that thecollagen-hydrogel material for promoting epithelial cell growth can beused as the base material for fabrication of artificial lens of areproducable power and quality as is well known in the art for producingcontact lens. The collagen-hydrogel artificial lens can be reproducedreliably in the laboratory and is not dependent upon the availability ofhuman tissue as is the case in the production of a corneal tissue lensas described by the prior art.

Another advantage of the present invention is that the artificial lensfabricated from the collagen-hydrogel for promoting epithelial cellgrowth of the present invention and implanted on the eye results in theelimination of rejection of the artificial lens by the cornea andpromotes and supports growth of epithelial cells during the healingprocess to actually implant the lens between Bowman's membrane and a newlayer of corneal epithelium grown from the epithelial cells.

Another advantage of the present invention is that the artificial lenscan be fabricated to any selected geometrical shape or diopter powerfrom the collagen-hydrogel for promoting epithelial cell growth usingany one of molding, lathing or freezing processes.

Another advantage of the present invention is that the collagen-hydrogelfor promoting epithelial cell growth enables corneal epithelium toattach to and cover the anterior surface of an artificial lens implantedwithin the eye because of the growth of epithelial cells which produce acorneal epithelium having several layers of cell thickness resulting inthe artificial lens being implanted between Bowman,s membrane andcorneal epithelium.

Another advantage of the present invention is that the implantation ofthe artificial lens requires only the removal of corneal epithelium fromthe surface of the cornea and the formation of a small "V" shaped slotand corneal wing which does not disturb the integrity of the cornea anymore than a corneal abrasion or a superficial corneal laceration. Theartificial lens is covered with epithelial cells during the healingprocess.

Another advantage of the present invention is that the necessity ofmaintaining a "tear layer" between the posterior surface of a softcontact lens and corneal epithelium is eliminated.

Another advantage of the present invention is that when the epithelialcells attach to and cover the anterior surface of an artificial lensfabricated from the collagen-hydrogel for promoting epithelial cellgrowth, if it ever becomes surgically necessary to remove and replacethe artificial lens, such as for example in an accident damaging theeye, the collagen-hydrogel can be stripped from Bowman's Membrane andcorneal epithelium can regrow over a defect, or a new collagen-hydrogelcan be placed which will support regrowth of corneal epithelium. This isone of the basic advantages of the Epikeratophakia Procedure. Thatadvantage is that a corneal overlay is less invasive to the eye than acorneal inlay.

Another advantage of the present invention is that the collagen-hydrogelfor promoting epithelial cell growth disclosed herein is formed by thefree radical polymerization of a hydrophilic monomer solution gelled andcrosslinked to form a three dimensional polymeric meshwork anchoringmacromolecules, comprising a constituent of a ground substance oftissue, which are interspersed within said polymeric meshwork forming acollagen-hydrogel for promoting epithelial cell growth.

Another advantage of the present invention is that the macromoleculesmay be a native collagen derived from animal sources and capable ofpromoting and supporting growth of epithelial cells.

Another advantage of the present invention is that the sources of nativecollagen can be harvested from tissues of human cornea, livestock corneaor calf's or livestock skins, all of which are widely available in analmost unlimited supply and at a reasonable cost.

Another advantage of the present invention is that the hydrogel can beformed from a hydrophilic monomer such as hydroxyethylemethacrylate.

Another advantage is that hydrogel can be polymerized in the presence ofa crosslinking agent to form a three dimensional polymeric meshworkhaving controlled spacings between the molecules thereof to anchor themacromolecules which have a known size and to insure that themacromolecules will be substantially uniformly interspersed within thepolymeric meshwork of the polymerized hydophilic monomer.

Another advantage of the present invention is that the step of formingthe crosslinking of the hydrogel can be performed with a crosslinkingagent which may be external, such as for example ultraviolet radiation,or a crosslinking agent added to the hydrogel clear viscous monomersolution, which crosslinking agent may be, for example, ethylene glycoldimethacrylate or methymethacrylate.

Another advantage of the present invention is that the artificial lenscan be formed of the collagen-hydrogel for promoting epithelial cellgrowth of the present invention wherein the artificial lens has anoptical portion configured for placement over the pupillary zone of theeye and on the central anterior surface of Bowman's membrane of thecornea having corneal epitheleum thereof removed. The optical portion ofthe artificial lens is dimensioned to substantially cover the totalanterior surface of the pupillary zone of an eye.

Another advantage of the present invention is that a method offabricating a collagen-hydrogel for promoting epithelial cell growthwhich, when positioned contiguous to Bowman's membrane and cornealepithelium of the cornea of an eye, promotes and supports epithelialcell growth to form a corneal epithelium is disclosed herein.

Another advantage of the present invention is that a method for locatingon the cornea an artificial lens having a preselected geometric shapeand power and including an optical portion having an outer edge, aposterior surface and an anterior surface is disclosed herein.

Another advantage of the present invention is that the method forlocating on the cornea an artificial lens having a preselected geometricshape and power includes the steps of removing from Bowman's membraneover the pupillary zone of the eye a portion of corneal epithelium on anarea slightly greater than the generalized shape of said artificiallens; forming on Bowman's membrane and corneal stroma a "v" shapedannular groove having a diameter substantially equal to the maximumgeometrical dimensions of the artificial lens and defining therearound aperipheral and medial edge and having a preselected depth which is lessthan the thickness of the corneal stroma; dissecting the peripheral edgeof said groove forming a wing of corneal tissue having a preselectedlength; separating the medial edge of the groove from the cornealgroove; placing the posterior surface of said artificial lens on theanterior surface of the cornea and positioning the outer edge of saidartificial lens under the corneal wing, and affixing the artificial lensto the cornea over the pupilary zone of the eye to maintain the same onthe cornea with the posterior surface in contact with Bowman's membraneand the corneal wing overlying the edge of the artificial lens enablingcorneal epithelium to touch and interact with said collagen-hydrogel forpromoting epithelial cell growth and to respond to said cell growthpromoting constituent in the collagen-hydrogel for promoting epithelialcell growth over a healing period where epithelial cells grow over andadhere to said artificial lens implanting the same in the cornea under anew growth layer of corneal epithelium.

Another advantage of the present invention is that the artificial lensformed of a collagen-hydrogel for promoting epithelial cell growth canbe implanted by using surgical procedures similar to those used incorneal overlays and corneal inlays which are easier to perform than theimplantation of a lens within the corneal stroma as taught by theSwinger/Barraquer Publication.

Another advantage of the present invention is that the step of suturingthe artificial lens to Bowman's membrane can be accomplished usingsuturing techniques presently in the art which include removablesuturing material, such as nylon, mersilene, or Prolene(polypropylene),or removable devices, such as staples, or biodegradable suturingmaterial, such as pos, vicrylor dexon, by use of the suturing techniquesdisclosed in U.S. Pat. No. 4,126,904 cited above, suturing throughopenings formed in the lens, by suturing around the edge thereof by useof a running stitch suturing method known as the "running shoe lace"stitch, suturing by use of individual or "interrupted" sutures, or byuse of a biodegradable adhesive which is applied to the posteriorsurface of an artificial lens formed of the collagen-hydrogel forpromoting epithelial cell growth disclosed herein. Also, the artificiallens could be held in place with presently available "therapeutic"contact lenses.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other advantages of this invention will be readily apparentwhen considered in light of the detailed description hereinafter of thepreferred embodiment and when considered in light of the drawing setforth herein which includes the following figures:

FIG. 1 is a block diagram of the method for producing thecollagen-hydrogel for promoting epithelial cell growth of the presentinvention;

FIG. 2 is a pictorial representation of an eye showing the relationshipbetween corneal epithelium, Bowman's membrane and the corneal stroma anda representation of an artificial lens formed of the collagen-hydrogelfor promoting epithelial cell growth which is adapted to be implantedwith the eye using the surgical procedures set forth herein;

FIG. 3 is a pictorial representation of an eye showing the relationshipbetween an implanted artificial lens shown in FIG. 2 implanted betweenBowman's membrane and corneal epithelium after the eye has healed andthe epithelial cells have grown to several layers in thickness and formcorneal epithelium which is attached to and covers the anterior surfaceof the artificial lens;

FIG. 4 is a cross sectional view of an eye illustrating that theimplanted artificial lens illustrated pictorially in FIG. 2 overlies thepupillary zone of the eye and that the same is in the form of a cornealinlay after the healing process;

FIG. 5 illustrates pictorially the first steps of the surgical procedureof removing a portion of corneal epithelium to expose a portion ofBowman's membrane and forming an annular shaped "V" groove wherein the"V" shaped groove has a peripheral edge and medial edge;

FIG. 6 illustrates pictorially that the area of removed cornealepithelium is generally circular in shape and that the "V" shaped grooveis located peripherally within the area of removed corneal epithelium;

FIG. 7 illustrates pictorially the corneal wing that is formed in theperipheral edge of the annular "V" shaped groove;

FIG. 8 illustrates the insertion of the edge of the artificial lensunder the corneal wing;

FIG. 9 illustrates pictorially the relationship of the edge of theartificial lens under the corneal wing after completion of the surgeryand before the healing process;

FIG. 10 illustrates pictorially the relationship of the edge of theartificial lens under the corneal wing after completion of the surgeryand after the healing process wherein the epithelial cells have grown toform corneal epithelium implanting the lens between Bowman's membraneand corneal epithelium;

FIG. 11 is a partial cross section showing the use of a removablesuturing material for affixing the artificial lens to the cornea afterthe lens has been positioned in place as illustrated in FIG. 10;

FIG. 12 is a representation of a circular shaped lens having twoopenings formed therein to permit the means for performing the suturingstep illustrated in FIG. 11;

FIG. 13 is a pictorial representation of a complete eye illustrating thesutured lens on the cornea;

FIG. 14 is a representation of a rectangular shaped artificial lenshaving an optical portion and edges which can be used to suture the lensin position over the pupillary zone of the eye;

FIG. 15 is a representation of a circular shaped artificial lens formedof the collagen-hydrogel for promoting epithelial cell growth of thisinvention and having an implanted ring of material having differentoptical properties than that of the collagen-hydrogel for promotingepithelial cell growth and which provides differential passage of animage to the retina and which is of a size and shape to be implanted onthe cornea using the teachings of this invention;

FIG. 16 is a representation of a circular shaped artificial lens formedfrom the collagen-hydrogel for promoting epithelial cell growthdisclosed herein having tabs extending therefrom which may be used by asurgeon in implanting the artificial lens in the eye using the teachingsof this invention;

FIG. 17 is a representation of a circular shaped artificial lens formedfrom the collagen-hydrogel for promoting epithelial cell growthdisclosed herein having two aligned circular support members extendingopposite direction therefrom which may be used by a surgeon inimplanting the artificial lens in the eye using the teachings of thisinvention; and

FIG. 18 is a representation of a circular shaped artificial lens formedfrom the collagen-hydrogel for promoting epithelial cell growthdisclosed herein having three circular tabs spaced equidistantly aroundthe periphery of an optical lens which may be used by a surgeon inimplanting the artificial lens in the eye using the teachings of thisinvention.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The block diagram of FIG. 1 illustrates the various steps of thepreferred method of fabricating a collagen-hydrogel for promotingepithelial cell growth when positioned contiguous to Bowman's membraneand corneal epithelium of the cornea of an eye. The method comprises thestep of forming a free radical polymerization of a hydrophilic monomerwhich is illustrated by block 20 of FIG. 1. The so formed hydrophilicmonomer solution used in the step of mixing with an aqueous solution ofmacromolecules comprising a constituent of ground substance of tissue inthe presence of a weak solution of ammonium persulfate and sodiummetabisulfate forming a clear viscous monomer solution as illustrated bybox 22 of FIG. 1. If the crosslinking agent is to be used to crosslinkthe polymer during this step, the crosslinking agent is added during themixing step to insure that the viscous monomer solution had acrosslinking agent therein such that the step of heating will cause thecrosslinking to occur to form the polymerized meshwork. The addition ofthe crosslinking agent to the monomer solution is illustrated by block26 of FIG. 1.

The next step of heating the viscous monomer solution is illustrated byblock 28 of FIG. 1. The heating occurs in the presence of a crosslinkingagent to polymerize the same into a three dimensional polymeric meshworkhaving macromolecules, which are constituent of ground substance oftissue interspersed within the three dimensional polymeric meshwork. Ifthe crosslinking agent was added to the monomer solution during themixing step as illustrated by blocks 22 and 26, then the crosslinkingand interspersing of the macromolcules with the polymeric structureoccurs during the heating. By controlling the temperature and heatingtime of the heating step, the macromolecules are substantiallyuniformally interspersed with the three dimensional polymeric meshwork.

Alternatively, the crosslinking can be obtained without the heatingstep, and without the crosslinking agent being in the viscous monomersolution, as is discussed hereinbelow.

If a crosslinking agent is not added to the monomer solution during themixing phase as described above, the crosslinking can be performed byirradiating the monomer solution during the heating phase with gamma orultraviolet irradiation. The gamma or ultraviolet irradiation causes thepolymerized solution to crosslink and form a three dimensional polymericmeshwork wherein the spaces between the crosslinked molecules of thepolymerized hydrophilic monomer contain the macromolecules interspersedtherein.

The collagen-hydrogel of this invention differs from those known in theprior art because of the crosslinking of the hydrogel into a threedimension meshwork for anchoring macromolecules capable of supportinganchor-dependent cell growth. Generally hydrogels per se are formed byforming a crosslinked polymer in an aqueous solution to gel thesolution. This can be done by free radical polymerization of hydrophilicmonomers, such as hydroxyethylmethacrylate (HEMA). This process is wellknown in the art and is described in Refojo, M. J. (1956), JournalApplied Polymer Science, 9, pages 3416-3426, and Holly, H. and Refojo,M. J. (1975), Journal of Biomedical Material Res., 9, page 315. Manyother hydrophilic monomers in addition to HEMA can be employed.

As noted hereinabove, the preferred macromolecule added to support cellgrowth is native collagen, a known substrate for good cell growth.Soluble collagen can be prepared by art-recognized techniques. Inaddition, other proteins are satisfactory as long as they will supportcell attachment and growth. One example of an additional protein knownto support cell growth is fibronectin.

Macromolecules in addition to proteins can also be added to thesehydrogels as long as they are capable of supporting growth of epithelialcells. Polysaccharides and mucopolysaccharides are one class of suchmacromolecules, and those skilled in the art will know others.

Small molecules are not employed because they can diffuse throughout thethree dimensional meshwork of the crosslinked hydrogel. Since one of therequirements is that the cell growth supporting molecules must beanchored in the meshwork of the hydrogel, only macromolecules are usedfor promoting growth of epithelial cells. The suitable macromoleculescan be water soluble or insoluble, with the former being preferred.

Hydrogel polymers formed by free radical polymerization of monomersolutions, which is the case for HEMA hydrogel, require crosslinking toform the three dimensional polymeric structure of meshwork to gel theaqueous solution. HEMA monomer solutions normally contain somedimethacrylate which can crosslink the gel structure. The addition ofcrosslinking agents such as ethylene glycol dimethacrylate to thepolymerization process can change the resultant hydrogel. Generally, theaddition of crosslinking agents tend to increase the rigidity andmechanical strength of the hydrogel. Addition of crosslinking agents,such as ethylene glycol dimethacrylate and methymethacrylate, to thepolymerization mixture in the presence of native collagen, still changesthe physical properties of the hydrogel, and such additions to thepolymerization mixture are compatible with the native collagen, andresult in the collagen-hydrogel which support growth of epithelialcells. Other known crosslinking agents that can be used satisfactorilyin producing the collagen-hydrogel include diacrylates anddimethacrylates or other divalent molecules.

The following examples are of methods for producing thecollagen-hydrogel for promoting growth of epithelial cells of thepresent invention.

EXAMPLE I

Polymers of hydroxyethyl methacrylate (HEMA) are prepared by the methodof Refojo, described hereinbefore.

Pepsin soluble collagen is prepared by stirring the ground shaved skinfrom a one week old calf in 0.5 M acetic acid at 4° C. The residue,after centrifugation, is resuspended in 0.5 M acetic acid containingporcine pepsin at a final enzyme-tissue ratio of 1:50 (wet weight) andallowed to stir overnight. The stabilized collagen is then precipitatedby addition of solid NaCl to a concentration of 5%. The resultingprecipitate is resolubilized in 0.5 M acetic acid, then dializedexhaustively versus 0.02 M Na₂ HPO₄, pH 7.44 at 4° C. Followingdialysis, the precipitate is subjected to differential NaClprecipitation at pH 7.44 as described in Chung, E. and Miller, E. J.(1974), Science. 183, pages 1200-1201. These precipitates are thenlyophilized and suspended in 0.5 M acetic acid at a concentration of1.2-1.4 mg/ml as determined by hydroxyproline content, and allowed tostir overnight at 4° C. The resulting solution is dialyzed against 0.15M NaCl-0.05 M Tris, pH 7.44, overnight at 4° C. This solution is used asa stock solution of collagen.

One ml of commercial HEMA, 1.0 ml of ethylene glycol, 1.0 ml of stocksolution of collagen (properly diluted), 0.1 ml of 6% ammoniumpersulfate and 0.1 ml of 12% sodium metabisulfate are added in sequence.A (quantity 0.1 ml of ethylene glycol dimethacrylate), a crosslinkingagent, is added to the solution. After mixing, the resulting clearviscous monomer solution is heated for two hours at 38° C., in a mold,as used in the production of a contact lens. The resulting clearflexible collagen-hydrogel is then dialyzed exhaustively versus theTris-NaCl buffer, pH 7.44, to remove residual monomer and ethyleneglycol. During dialysis, the collagen-hydrogel membranes become opaque,but transparency returns once the ethylene glycol has been exchanged forwater.

EXAMPLE II

A collagen-hydrogel monomer viscous solution is prepared as in EXAMPLE Iexcept that the ammonium persulfate and sodium metabisulfate are notadded to the solution. The collagen-hydrogel is exposed to gammaradiation or ultra violet radiation for two hours to polymerize themonomer solution. The resulting collagen-hydrogel, is sterilized inPuck's Ca⁺⁺ Mg⁺⁺ free saline containing 1,000 units penicillin, 50 mlAureomycin, and 0.25 ml Fungizoine per ml of medium and placed under anultraviolet light for two hours. The collagen-hydrogel is thentransferred to a Puck's saline containing penicillin and streptomycinand stored at 4° C. prior to use.

EXAMPLE III The White Cat Study

A White Cat Study was performed on a normal cat which was white incolor. The purpose of the experiment and study was to implant anartificial lens using the teachings of the collagen-hydrogel inventioninto one eye of the subject cat to determine to what extent that thecollagen hydrogel enhanced epithelial cell growth.

(A) Preparation of collagen hydrogel material and artificial lens fromthe collagen hydrogel material

The artificial lens utilized in the White Cat Study was fabricated froma collagen hydrogel material prepared in accordance with the method ofExample I above.

The collagen-hydrogel material was prepared using 10 milligrams ofcollagen per milliter of collagen stock solution. The collagen used wasa type 8 placentia collagen. The mixture was polymerized between twoglass slides to form a generally planar rectangular sheet having athickness of about 0.5 millimeters to about 1.0 millimeters. Oneartificial lens was cut from the generally planar rectangular sheethaving a generally rectangular shape. The dimensions of the artificiallens cut from the sheet of material was approximately 6 millimeters inlength, approximately 3 millimeters in width and about 5 millimeters toabout 1.0 millimeters in thickness. The physical characteristics of thelens were that it had the appearance of a clear plastic sheet, wassmooth, transparent and optically clear.

(B) Method of surgery for affixing an artificial lens fabricated fromthe collagen hydrogel material to one eye of a white cat

The surgical procedure for affixing the artificial lens fabricated fromthe above described collagen hydrogel material to the subject white catwas performed in a standard operating room. The subject white cat wasanesthetized using standard procedures. After the anesthesia becameeffective, the initial step performed was to remove the epithelium layerfrom the cornea. This step was performed by scraping off the epithelialcells located in the center of the eye forming a generally square areaof about 8 millimeters by 8 millimeters. A rectangular shaped artificiallens was prepared from the sheet of material and the dimensions of theartificial lens was approximately 6 millimeters in length, approximately3 millimeters in width and about 0.5 millimeters to about 1.0millimeters in thickness.

The cornea was then prepared surgically using the steps of the methoddescribed in the connection with FIGS. 5 through 9 hereof. Theartificial lens was inserted under the corneal wing and sutured in placeusing a 10-nylon suture forming 8 uninterrupted stitches. The thirdeyelid or nictating membrane of the subject cat was pulled over thecornea a stitched in the closed position to prevent the cat fromsubsequently traumatizing the eye. The subject white cat was then placedin a cat pound for a period of about one week to permit the lens tobecome implanted by the growth of epithelial cells. After the expirationof about one week, the subject cat was sacrificed and the one eye havingthe artificial lens affixed thereto was surgically removed, as anucleared eye, for an eye histologic procedure.

(C) Results of eve histologic procedure of an artificial lens fabricatedfrom the collagen hydrogel material affixed to one eye of a white cat

The one eye having the artificial lens affixed thereto that wassurgically removed for the eye histologic procedure was placed into astandard foramalin solution. The analysis of the nucleared eye wasperformed using standard pathological procedures for the fixation of theeye. The global area of the eye disclosed that the cornea was curved,that the artificial cell was in place, that the artificial lens wasclear and that the cornea was clear. An examination of a tissue sampleof the cornea disclosed that the epithelial cells had grown over andimplanted the artificial lens. Also, it further noted that the stroma hdalso regenerated and had grown over the edge of and became attached tothe artificial lens. The regeneration of the stroma was unexpected. Theexamination of the stroma further disclosed that the eye hadhematoxyalineosin present in the stroma. An examination of the layers ofthe stroma disclosed that new keratocytes, i.e. cells that producecollagen, were present in the laminated layers of the stroma. As aresult of the presence of the keratocytes, collagen fibial, i.e.molecules produced by keratocytes, were laid down in the laminatedlayers of the stroma. The results clearly showed that: (a) epithelialcell growth occurred over and implanted the artificial lens into thecornea; and (b) the stroma was regenerated and the keratocytes weregrowing over and attaching to the edge of the artificial lens andproducing collagen fibial or collagen molecules.

EXAMPLE IV The Black Cat Study

The Black Cat Study was performed on a normal cat which was black incolor. The purpose of the experiment and study was to implant anartificial lens using the teachings of the collagen-hydrogel inventioninto one eye of the subject cat to determine to what extent that thecollagen hydrogel enhanced epithelial cell growth.

(A) Preparation of collagen hydrogel material and artificial lens fromthe collagen hydrogel material

The artificial lens utilized in the Black Cat Study was fabricated froma collagen hydrogel material prepared in the same manner as thatdescribed above for the White Cat Study of Example III above.

The sheet of collagen hydrogel material likewise had a thickness ofabout 0.5 millimeters to about 1.0 millimeters. The dimensions of theartificial lens cut from the sheet of material was approximately 6millimeters in length, approximately 3 millimeters in width and about0.5 millimeters to about 1.0 millimeters in thickness. The physicalcharacteristics of the lens were that it had the appearance of a clearplastic sheet, was smooth, transparent and optically clear.

(B) Method of surgery for affixing an artificial lens fabricated fromthe collagen hydrogel material to one eye of a black cat

The surgical procedure for affixing the artificial lens fabricated fromthe above described collagen hydrogel material to the subject black catwas substantially the same as that described hereinbefore for the whitecat in The White Cat as described in Example III above. The initial stepof removing the epithelium layer from the cornea was performed byscraping off the epithelial cells located in the center of the eyeforming a generally square area of about 12 millimeters by 8millimeters. A rectangular shaped artificial lens was prepared from thesheet of material and the dimensions of the artificial lens wasapproximately 6 millimeters in length, approximately 3 millimeters inwidth and about 0.5 millimeters to about 1.0 millimeters in thickness.

The cornea was then prepared surgically, the artificial lens wasinserted under the corneal wing and sutured in situ in substantially thesame manner as described above for the white cat in The White Cat Studyof Example III above. The subject black cat was then placed in a catpound for a period of about one month to permit the lens to becomeimplanted by the growth of epithelial cells. After the expiration ofabout one month, the subject cat was sacrificed and the one eye havingthe artificial lens affixed thereto was surgically removed, as anucleared eye, for an eye histologic procedure.

(C) Results of eye histologic procedure of an artificial lens fabricatedfrom the collagen hydrogel material affixed to one eye of a black cat

The one eye having the artificial lens affixed thereto, that wassurgically removed for the eye histologic procedure, was placed into astandard foramalin solution and a standard pathological procedure forthe fixation of the eye was performed in substantially the same manneras described above for the white cat in The White Cat Study as describedabove in Example III. The analysis disclosed that the in the global areaof the eye that the cornea was curved, that the artificial cell was inplace, that the artificial lens was clear and that the cornea was clear.The examination disclosed that the eye had been subject to some traumain that the third eyelid or nictating membrane of the subject cat, whichinitially had been pulled over the cornea a stitched in the closedposition to prevent the cat from subsequently traumatizing the eye, hadbeen ruptured and the third eyelid permitted the cornea to be exposed ina sufficient manner for the subject black cat to traumatize the eye.

However, an examination of a tissue sample of the cornea disclosed thatthe epithelial cells had grown over and implanted the artificial lens.Also, it further noted that the stroma had also regenerated and hadgrown over the edge of and became attached to the artificial lens. Theexamination of the stroma further disclosed that the eye hadhematoxyalineosin present in the stroma and that regeneration of thestroma had also occurred in the black cat. An examination of the layersof the stroma disclosed that new keratocytes, i.e. cells that producecollagen, were present in the laminated layers of the stroma. As aresult of the presence of the keratocytes, collagen fibial, i.e.molecules produced by keratocytes, were laid down in the laminatedlayers of the stroma. The results clearly showed that: (a) epithelialcell growth occurred over and implanted the artificial lens into thecornea; and (b) the stroma was regenerated and the keratocytes weregrowing over and attaching to the edge of the artificial lens andproducing collagen fibial or collagen molecules.

EXAMPLE V

A collagen-hydrogel monomer viscous solution is prepared as in EXAMPLE Iexcept that an epithelial cell growth enhancer is added to thecollagen-hydrogel monomer viscous solution before heating andpolymerization. The amount of epithelial cell growth enhancer that couldbe added by weight could be as low as a trace of epithelial cell growthenhancer or could be in the order of the weight of collagen asdetermined by the ratio by weight of the collagen in thecollagen-to-hydrogel weight or higher depending on the material. Themaximum amount of epithelial cell growth enhancer that could be added isthat amount which would make the collagen-hydrogel material cloudy and,thus impair the transparency of the collagen-hydrogel material oroptical lens made therefrom. This would result in the epithelial cellgrowth enhancers being interspersed throughout the polymerized material.

Examples of epithelial cell growth enhancers are: (a) the epithelialgrowth factor molecule such as, for example an epithelial growth factormolecule isolated by Chiron Ophthalmics, Inc. and used for to produce amore rapid resolution of corneal abrasion; or (b) Fibronectin, amacromolecule which enhances epithelial cell growth.

EXAMPLE VI

A collagen-hydrogel monomer viscous solution is prepared as in EXAMPLEI. If desired, an optical lens or artificial lens can be fabricated fromthe collagen-hydrogel material as described herein either before orafter treatment with an epithelial cell growth enhancers. Either thecollagen-hydrogel material, prior to fabrication of an optical lens orartificial lens therefrom or the optical lens or artificial lensfabricated from the collagen-hydrogel material is soak in a solutioncontaining the epithelial cell growth enhancers in sufficientconcentration to cause the molecule of the epithelial cell growthenhancers to permeate the outer layer of material forming a thin layerof epithelial cell growth enhancer on the exterior outer surface or toenable molecules of the epithelial cell growth enhancers to attached toand be supported by the outer surface of the collagen-hydrogel material.

EXAMPLE VI

The preferred embodiment of the collagen-hydrogel material forpractising this invention is to prepare the collagen-hydrogel materialas set forth in Example I wherein the volumes of the componentscomprise:

1 millimeter of a stock solution of collagen;

1 millimeter of HEMA;

1 millimeter of ethylenically unsaturated monomeric units;

0.1 millimeter of ammonium persulfate; and

0.1 millimeter of metabisulfate

wherein the ammonium persulfate and metabisulfate are catalysts.

(End of examples)

Based on the above examples, a calculation of the weight of collagen inthe collagen-hydrogel material has a ratio by weight ofcollagen-to-hydrogel in the range of about 0.6-to-1000. This is theupper limit of the ratio by weight in that a greater ratio by weight ofcollagen-to-hydrogel may result in the material becoming cloudy therebyrendering the material undesireable for fabricating an artificial lensor optical lens therefrom. Thus, the collagen-hydrogel material can havea ratio by weight which is less than 0.6-to-1000, but at a level whereinsufficient collagen is present in weight to at least one of promoteepithelial cell growth and regeneration of the stroma to producekeratocytes including collagen fibial growth.

A person skilled-in-the-art could, likewise, calculate the mole percentof each of the components in the composition.

Collagen-hydrogel which contain HEMA alone, or HEMA, ethylene glycoldimethacrylate and methymethacrylate, and all combinations thereof, instrata, support various other cell growth lines in tissue culture.Specifically, the so formed collagen-hydrogels successfully supportedgrowth of the following cell lines:

(1) Rabbit smooth muscle cells;

(2) Calf smooth muscle cell;

(3) Lung endothelial cells;

(4) Lung epithelial

(5) Epithelial Cells; and

(6) Regeneration of the stroma to produce keratocytes including collagenfibial growth.

It is likely that the collagen-hydrogel disclosed herein can serve tostrata for growth of all cells of all classes, epithelial, endothelialand mesothelial, which appear to be compatible with cells of alltissues, including corneal epithelial cells.

FIG. 2 illustrates pictorially the method of positioning an artificiallens, fabricated from the collagen-hydrogel as described above, andformed of a predetermined geometrical shape and lenticular power, suchas a contact lens, to the cornea. The eye, shown generally as 40, has acorneal epithelium 42 formed of layers of epithelial cells illustratedgraphically as humps 46. Below corneal epithelium 42 is Bowman'smembrane 48, which supports corneal epithelium. Below Bowman's membraneis the corneal stroma 50. An artificial lens, such as for example acontact lens having an optical portion, 60 is positioned above cornealepithelium to illustrate the size thereof.

FIG. 3 illustrates pictorially the preferred location of the contactlens 60 in the eye after the healing process. The contact lens 60 islocated between Bowman's membrane and corneal epithelium after newepithelial cells 52 have grown during the healing process to cover theanterior surface of the lens 60.

FIG. 4 illustrate that the contact lens is positioned over the pupillaryzone 62 of the eye and implanted between Bowman's membrane 48 andcorneal epithelium 42.

FIGS. 5 through 10 disclose a method for locating on the cornea anoptical lens, which may be an artificial lens such as a contact lens,having a preselected geometric shape and lenticular power wherein theoptical lens comprises an optical portion having an outer edge 66, ananterior surface 70 and a posterior surface 72, the elements 66, 70 and72 being shown in FIG. 2. For purposes of the steps illustrated in FIGS.5 through 10, the artificial lens has been fabricated from thecollagen-hydrogel, and the specific contact lens has been formed by (i)a contact lens mold, or (ii) frozen collagen-hydrogel which has beenlathed, so as to form a contact lens of a predetermined shape and power.Prior to placement of the lens on the cornea, the contact lens issterilized by exposure to ultraviolet light.

FIG. 5 illustrates the first step of the surgical method, that stepbeing the removing from Bowman's membrane 40, over the pupillary zone ofthe eye, a portion of corneal epithelium on an area slightly greaterthan the generalized shape of said optical lens, which area isrepresented by area 76. This step is similar to the removal of cornealepithelium from the anterior surface of the cornea in theEpikeratophakia Procedure.

Thereafter, the next step is that of forming on Bowman's membrane 40 a"V" shaped annular groove 78 having a diameter substantially equal tothe maximum geometrical dimensions of the optical lens 60 and definingtherearound a peripheral edge 80 and a medial edge 82. The "V" shaped,annular groove 78 has a preselected depth which is less than thethickness of the corneal stroma 50. Typically, the groove is formed tohave a depth of about 0.3 mm, and the depth is prepared in the corneautilizing a 7 mm trephine.

FIG. 6 illustrates, by means of a front view, the cornea showing thearea 76 of corneal epithelium 46 that has been removed from and toexpose the area of Bowman's membrane 40 from which corneal epithelium 46has been removed. Also, the annular shape of the "V" groove 78 isillustrated.

FIG. 7 shows the next step of dissecting the peripheral edge 80 of thegroove 78 forming a wing 88 of corneal tissue having a preselectedlength. This step is performed by the surgeon in the following manner.As in an Epikeratophakia Procedure, a corneal-spreading instrument isused to dissect the peripheral edge 80 of the groove 78 forming acorneal wing, preferably of about 1.5 mm in length. The edge 66 of theoptical lens 60 is to be located under the corneal wing 88. The medialedge 82 is cut free of the globe, i.e. the curved surface of Bowman'smembrane 40.

FIG. 8 illustrates the next step of placing the posterior surface 72 ofthe optical lens 60 on the anterior surface of Bowman's membrane andpositioning the outer edge 66 of the optical lens 60 under the cornealwing 88.

FIG. 9 illustrates the final position of the lens 60 over the pupillaryzone of the eye before the optical lens is attached to or affixed to theeye. The attachment can be performed in any number of procedures, one ofwhich is illustrated in FIG. 11. FIG. 9 is then a representation of theoptical lens in the eye at the end of the surgical procedure, and beforethe healing process. It is pointed out that the anterior surface of thelens 60 is free of any cell growth. As illustrated in FIG. 9, the edge66 of the lens 60 is positioned relative to and in contact with cornealepithelium 42 and the corneal wing 88 lies flush with the anteriorsurface of the optical lens 60.

FIG. 10 is a representation of the condition of the eye at the end ofthe healing process.

As shown in FIG. 10, the edge 66 of the lens 60 is positioned so as toenable the epithelial cells to touch and interact with thecollagen-hydrogel lens 60 to promote epithelial cell growth over ahealing period. During the healing period, new epithelial cells 52 growover and adhere to the anterior surface 70 of the optical lens 60,implanting the same in the cornea under a new growth of cornealepithelium 42 formed from several layers of new epithelial cells.

FIG. 11 illustrates one method of suturing a lens to Bowman's membranewherein the optical lens includes at least two openings therein adjacentthe outer edge thereof. Such a lens is illustrated in FIG. 12 as lens 90having openings 92 and 94. As illustrated in FIG. 11, the lens 90 isaffixed to Bowman's membrane by the step of suturing the optical lens 90to Bowman's membrane through the openings 92 and 94. The suture materialis shown as a single loop stitch 100 in FIG. 11.

In the alternative, the lens 60, illustrated in FIGS. 9 and 10, could beaffixed to Bowman's membrane by the step of bonding with a biodegradableadhesive the posterior surface 72 of the optical lens to Bowman'smembrane 40.

The method of affixing the lens to Bowman's membrane can be accomplishedwith either a removable or biogradable suturing material, staples or thelike. One preferred method for insuring that the lens 90 does notseparate from Bowman's surface resulting in the edge 96 moving fromunder the corneal wing 88 is to utilize the step of suturing the opticallens 90 to Bowman's membrane with a biodegradable suturing material inthe form of a running "shoe lace" stitching which passes through theouter edge of the optical lens 90 and Bowman's membrane 40.

FIG. 13 illustrates in a front view, after completion of locating thelens on the cornea of the eye and before beginning the healing process,the relationship of the eye 90 to the cornea wherein the lens 90, ofFIGS. 11 and 12, is sutured to Bowman's membrane through openings 92 and94 of the lens 90.

FIG. 14 illustrates a possible lens configuration for an artificial lens110 having an optical portion 112 configured for placement over thepupillary zone of the eye and on the central anterior surface ofBowman's membrane of the cornea having corneal epithelium thereofremoved. The optical portion terminates in end tabs 114 and is formedsuch that the optical portion is dimensioned to substantially cover thetotal anterior surface of the pupillary zone of an eye. The entire lens110 including the optical portion 112 and tabs 114 is formed of acollagen-hydrogel for promoting epithelial cell growth.

FIG. 15 is a representation of a circular shaped artificial lens 120formed of the collagen-hydrogel for promoting epithelial cell growth andhaving implanted therein a ring 122 of material having different opticalproperties than that of the collagen-hydrogel for promoting epithelialcell growth used in the lens 120. The ring 122 functions to focus at thecenter thereof while the outer edge of the ring 122 passes light to theretina. This results in a differential passage of an image to theretina. The lens 120 is of a size and shape to be implanted on thecornea using the teachings of this invention.

FIG. 16 is a representation of a circular shaped optical portion 124 ofan artificial lens formed from the collagen-hydrogel for promotingepithelial cell growth disclosed herein having tabs 126 extendingtherefrom which may be used by a surgeon in implanting the artificiallens in the eye using the teachings of this invention. The opticalportion 124 and the tabs 126 are formed of the collagen-hydrogel.

FIG. 17 is a representation of a circular shaped artificial lens havingan optical portion 130 formed from the collagen-hydrogel for promotingepithelial cell growth disclosed herein and two aligned circular supportmembers 132 extending in opposite directions from the optical portion130 which may be used by a surgeon in implanting the artificial lens inthe eye using the teachings of this invention. The optical portion 130and the tabs 132 are formed of the collagen-hydrogel.

FIG. 18 is a representation of a circular shaped artificial lens formedfrom the collagen-hydrogel for promoting epithelial cell growthdisclosed herein wherein the optical portion 140 has three circular tabsor support members 142 having apertures formed therein spacedequidistantly around the periphery of an optical lens portion 140. Thesupport members 142 may be used by a surgeon in implanting theartificial lens in the eye using the teachings of this invention. Theoptical portion 130 and the tabs 132 are formed of thecollagen-hydrogel.

It is envisioned that the collagen-hydrogel of the present invention,and artificial lens formed from the collagen-hydrogel, can be used forepicorneal, corneal or transcorneal lenses which are capable ofpromoting and supporting epithelial cell growth during the healingperiod. During the healing process, a bandage contact lens may be placedon the eye until the anterior surface of the lens is covered by cornealepithelium.

The collagen-hydrogel biomedical material disclosed herein has, in itspreferred embodiment, application in the artificial lens field becauseof the properties of the collagen-hydrogel promoting the growth ofepithelial cells. It is envisioned that such collagen-hydrogel could beused as substrata for support of growth of other cells in the human bodywherein the hydrogel could be formed of any one of a number of monomersof the hydrophilic class of polymers, and that other so formed hydrogelswhen used in a collagen-hydrogel with appropriate macromolecules asdescribed herein could be used to enable the growth of other classes ofhuman tissue other than epithelial cells.

What is claimed is:
 1. A method for locating on the cornea an opticallens having a preselected geometric shape and power, said optical lenscomprising an optical portion having an outer edge, a posterior surfaceand an anterior surface, said optical lens being formed of a hydrogelpolymer formed by the free radical polymerization of a hydrophilicmonomer solution gelled and crosslinked to form a three dimensionalpolymeric meshwork for anchoring collagen; and a stock solution ofcollagen added to and interdisposed within said polymeric meshworkforming a collagen-hydrogel for promoting epithelial cell growth andregeneration of the stroma wherein said collagen-hydrogel material has aratio by weight of collagen-to-hydrogel in the range of about0.6-to-1000 and less than 0.6-to-1000 but at a level wherein sufficientcollagen is present by weight to at least one of promote epithelial cellgrowth and regeneration of the stroma comprising the steps of:removingfrom Bowman's membrane over the pupillary zone of the eye a portion ofcorneal epithelium on an area slightly greater than the generalizedshape of said optical lens; forming on Bowman's membrane a "v" shapedannular groove having a diameter substantially equal to the maximumgeometrical dimensions of said optical lens and defining therearound aperipheral edge and medial edge and having a preselected depth which isless than the thickness of the corneal stroma; dissecting the peripheraledge of said groove forming a wing of corneal tissue having apreselected length; placing the posterior surface of said optical lenson the anterior surface of Bowman's membrane and positioning the outeredge of said optical lens under said corneal wing, whereby the cornealwing lies flush with and in contact with the anterior surface of saidlens; and affixing the optical lens to the Bowman's membrane over thepupillary zone of the eye to maintain the same on the cornea with theposterior surface in contact with Bowman's membrane and the corneal wingoverlying the edge of said optical lens enabling corneal epithelium totouch and interact with said optical lens formed of a stock solution ofcollagen added to a hydrogel polymer for promoting epithelial cellgrowth and adherence to said optical lens and to respond to theepithelial cells growth promoting constituent in said optical lensformed of a stock solution of collagen added to a hydrogel polymer overa healing period wherein epithelial cells grow in from the edge of saidoptical lens and over the same enabling the epithelial cells to adhereto and implant said optical lens in the cornea under a new growth ofcorneal epithelium formed from several layers of epithelial cellsadhering to the optical lens and the stroma has regenerated in thevicinity of the optical lens.
 2. The method of claim 1 wherein thepredetermined depth of the "V" shaped groove is surgically formed to beabout 0.3 mm and the predetermined length of the corneal wing issurgically formed to be about 1.5 mm.
 3. The method of claim 1 whereinsaid optical lens includes an outer edge and wherein said steps ofaffixing the optical lens to the cornea comprises the step ofsuturingthe optical lens to said Bowman's membrane.
 4. The method of claim 3wherein the step of suturing includes the use of biodegradable sutures.5. The method of claim 3 wherein the step of suturing includes the useof non-biodegradable sutures.
 6. The method of claim 1 wherein the stepof affixing the optical lens to the cornea comprises the steps ofbondingwith a biodegradable adhesive the posterior surface of the optical lensto the Bowman's membrane.
 7. The method of claim 1 wherein the step ofaffixing the optical lens to the cornea comprises the step ofsuturingthe optical lens to said Bowman's membrane with a biodegradable suturingmaterial in the form of a "running shoe lace" stitching which passesthrough the outer edge of said optical lens and said Bowman's membrane.8. The method of claim 1 wherein the step of affixing the optical lensto the cornea comprises the step ofsuturing the optical lens to saidBowman's membrane with a biodegradable suturing material in the form ofan interrupted stitching which passes through the outer edge of saidoptical lens and said Bowman's membrane.
 9. The method of claim 1wherein the step of affixing the optical lens to the cornea comprisesthe step ofholding the lens in place under the corneal wing with abandage or a therapeutic contact lens until the epithelium grows overthe collagen hydrogel.
 10. The method of claim 1 further comprising thestep of:severing the medial edge from the curved surface of the Bowman'smembrane.